First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic “cycling” of KRAS between its GDP- and GTP-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report D3S-001, a next generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as EGF and HGF, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust anti-tumor activity preclinically and translated into promising clinical activity in an ongoing phase 1 trial (NCT05410145).

中文翻译：

---

D3S-001 是一种具有快速靶标结合动力学的 KRAS G12C 抑制剂，可克服核苷酸循环并表现出强大的临床前和临床活性


第一代 KRAS G12C 抑制剂，如索托拉西和阿达拉西，受到临床反应深度和持续时间的限制。其临床活性不高的一个可能解释是 KRAS 在 GDP 结合状态和 GTP 结合状态之间动态“循环”，这引发了关于针对 GDP 结合形式是否可以完全阻止这一致癌驱动因素的争议。我们在此报道 D3S-001，一种下一代 GDP 结合的 G12C 抑制剂，具有更快的靶点结合 (TE) 动力学，可在纳摩尔浓度下耗尽细胞活性 KRAS G12C。在存在 EGF 和 HGF 等生长因子的情况下，sotorasib 和 adagrasib 抑制 KRAS 的能力受到损害，而 D3S-001 的 TE 动力学几乎不受影响，这是 D3S-001 与其他 GDP 结合 G12C 抑制剂的独特之处。此外，D3S-001 的高共价效力和细胞 TE 效率有助于在临床前发挥强大的抗肿瘤活性，并在正在进行的 1 期试验 (NCT05410145) 中转化为有前景的临床活性。